Molecular characterization of a mosaic NIPBL deletion in a Cornelia de Lange patient with severe phenotype
Articolo
Data di Pubblicazione:
2013
Citazione:
Molecular characterization of a mosaic NIPBL deletion in a Cornelia de Lange patient with severe phenotype / C. Gervasini, I. Parenti, C. Picinelli, J. Azzollini, M. Masciadri, A. Cereda, A. Selicorni, S. Russo, P. Finelli, L. Larizza. - In: EUROPEAN JOURNAL OF MEDICAL GENETICS. - ISSN 1769-7212. - 56:3(2013 Mar), pp. 138-143. [10.1016/j.ejmg.2012.12.009]
Abstract:
neurodevelopmental syndrome characterized by growth retardation, intellectual disability, dysmorphic
facial features, multisystem malformations, and limb reduction defects. Wide variability of phenotypes is
common among CdLS patients. Mutations in genes encoding either regulators (NIPBL, HDAC8) or subunits
(SMC1A, SMC3, RAD21) of the cohesin complex, are altogether found in approximately 65% of CdLS
patients.
We describe a CdLS patient with classic severe phenotype who was found negative to mutations in the
NIPBL and SMC1A genes by DHPLC and direct sequencing. MLPA analysis performed to disclose potential
intragenic NIPBL deletions/duplications, suggested a partial deletion which was confirmed by FISH with
a BAC clone encompassing the NIPBL region that highlighted asymmetric signals in a fraction of cells
(72%). The occurrence of a genomic deletion in mosaic condition was validated by array-CGH analysis.
Long-range PCR and sequencing of the junction fragment mapped the telomeric and the centromeric
breakpoint within NIPBL IVS1 and IVS32, respectively. Both deletion breakpoints were embedded in
a microsatellite region that might be the motif directly mediating this large deletion by an intrachromatid
recombination mechanism.
Consistent with the molecular analyses, the patient displayed a severe phenotype that was characterized
by drastic CdLS clinical signs including premature death. This case provides a second example of
mosaicism in CdLS. Despite mitigated by mosaicism, the large intragenic deletion identified in the
present case was poorly tolerated due to the high mosaicism level. Based on these data, overlooked cases
of mosaicism may lead to underestimated mutation rates of known genes and may also contribute to the
clinical heterogeneity of CdLS.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
CdLS ; NIPBL deletion ; mosaicism ; MLPA ; FISH ; Array-CGH ; deletion junction
Elenco autori:
C. Gervasini, I. Parenti, C. Picinelli, J. Azzollini, M. Masciadri, A. Cereda, A. Selicorni, S. Russo, P. Finelli, L. Larizza
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